Diltiazem
((25-cis-3-(Acetoxyl)-5-[2-(dimethylamino)ethyl]-2-3-dihydro-2-(4-methoxyph enyl)-1,5-benzothiazepin-4(5H)-one) is a safe and effective treatment for both stable and unstable angina pectoris (1). A variety of formulations containing diltiazem or diltiazem hydrochloride are available, as will be described below. These formulations provide a range of dose regimens, ranging from dosing as often as four times daily ("q.i.d."); twice daily ("b.i.d."), such as approximately every 12 hour, or once-daily ("q.d."). Patient compliance with the dosing regimens has been a factor in the development of the sustained or extended release formulations, enabling the twice-daily or once-daily dosing.
CARDIZEM CD (TM) is a once-a-day extended release formulation of diltiazem hydrochloride sold by Marion Merrill Dow Corporation, Kansas City, Mo., and which is prescribed for treatment of hypertension and angina (2).
DILACOR XR (TM) is an extended release formulation of diltiazem hydrochloride sold by Rhone-Poulenc Rorer Pharmaceuticals, Inc., Collegeville, Pa. Capsules of DILACOR XR (TM) contain a controlled release formulation of diltiazem that is designed to release the drug over a 24 hour period, using a controlled release system marketed under the trademark GEOMATRIX (registered to Jago Research AG (Zollikon, Switzerland) (3).
Diltiazem OD ER (Once-a-Day, Extended Release as described in the literature) is an extended release formulation of diltiazem sold in the U.S. under the trade name TIAZAC (TM) by Forest Pharmaceuticals, Inc., St. Louis, Mo., and approved for treatment of hypertension (4).
Diltiazem hydrochloride is also commercially available in the powder form from chemical supply companies such as Sigma Chemical Corp., St. Louis, Mo.
Panoz et al. (including Geoghegen as a coinventor, see below) in U.S. Pat. No. 4,721,619 (the "'619 patent") describe a controlled absorption diltiazem formulation intended for twice daily usage. The formulation includes a core containing diltiazem, and a multi-layer membrane surrounding the core. The composition of the water insoluble and water soluble polymer mixture used in the membrane, and the number of layers of membrane surrounding the core, affect the release rate of the drug from the core over a twelve hour period following oral administration. Peak plasma levels were obtained approximately 9-12 hours after administration of the formulation described in the '619 patent.
Geoghegen et al., in U.S. Pat. Nos. 4,894,240; 4,917,899; 5,002,776; and 5,616,345 describe controlled absorption formulations for diltiazem, based upon the formulation described in the '619 patent. In U.S. Pat. No. 4,894,240 the formulation is designed for once-daily administration and provides maximal release of diltiazem approximately 10-14 hours after oral administration.
The formulation described in U.S. Pat. No. 4,917,899 is characterized by its maximum release of diltiazem approximately 9 hours after administration. This formulation includes a mixture of slow release and fast release pellets of diltiazem, the fast release pellets having a thinner coating than that of the slow release pellets.
Hendrickson et al., in U.S. Pat. No. 5,286,497 (the "'497 patent"), U.S. Pat. Nos. 5,439,689 and 5,470,584 describe a diltiazem formulation intended for once-daily administration. These formulations contain a mixture of two types of beads, described as a rapid release bead and a delayed release bead. As described in the '497 patent, when tested separately, the rapid release beads reach their maximal release of drug within 6-8 hours after oral administration, with the delayed release bead reaching its maximal release of drug within 16-24 hours post-administration. The beads contain a core comprising diltiazem and may contain conventional pharmaceutical excipients, while the coating of the beads is a polymer that envelopes or substantially envelopes the core, thereby effecting the controlled release characteristics of the drug from the core. As described in the '491 patent, this formulation follows a "stair step" pattern of drug release, achieving a first maximum level of drug release at approximately 6-8 hours, and a second maximal level of drug release after approximately 21 hours in in vitro dissolution tests. When administered to humans, the formulation achieved a maximum plasma level at approximately 6-8 hours post-administration, with plasma levels dropping slowly for the next ten hours.
In U.S. Pat. No. 5,508,040 Chen describes a multiparticulate pulsatile drug delivery system, containing a plurality of pellets or particles that are made up of two or more populations of pellets or particles. The particle populations each contain a core or bead containing the drug to be delivered, and a polymer film coating surrounding the core. The thickness of the coating surrounding the core controls the rate of release of the drug into its environment of use, such as the stomach. The result is a pulsatile manner of drug delivery: the drug is released from a first population of pellets over a time period of approximately 4.5 hours after administration, its maximum release occurring at approximately 3 hours, and falling to base line levels by 4.5 hours; the second population of pellets starts releasing drug at approximately 3 hours after administration, peaking out at approximately 6 hours, and falling to base line levels at approximately 7.5 hours, and in embodiments where a third population of pellets is contained in the formulation, the release of drug from the third population follows the same 4.5 hour distribution pattern as the first two particle populations, only the start of drug release is delayed. When shown graphically, the quantity of drug released as a function of time post-administration is characterized by rising and falling drug levels. Consequently, the curve shows both peaks and valleys as a function of time after administration, corresponding to the rising and falling levels of the released drug.
Studies have shown that angina attacks occur in a diurnal cycle, and their occurrence is common in the hours shortly after an individual commences activity after waking. These studies will be described further in the INTRODUCTION section of the Description of the Invention, below. In view of the fluctuations of drug levels observed, or the delay seen in obtaining peak drug levels, with certain extended release diltiazem formulations, and the short time between waking and the onset of angina attacks, there is a need for a diltiazem formulation that will rapidly achieve therapeutic drug levels, and maintain them over a prolonged period, thereby improving both clinical efficacy and patient compliance with the dosage regimen.